Scalable and cost-effective CAR-T exosome therapies: challenges and future directions.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized hematological cancer treatment but faces challenges in solid tumors, including poor infiltration, cytokine release syndrome (CRS), and toxicity. CAR-T cell-derived exosomes (CAR-T exosomes) offer a promising alternative by inheriting CAR-mediated targeting and cytotoxic molecules (e.g., perforin, granzyme B), while avoiding issues such as CRS. Their nanoscale size enhances tumor penetration, and the lack of MHC reduces immunogenicity, which supports "off-the-shelf" applications. However, scalability remains limited by low yields from traditional isolation methods [e.g., ultracentrifugation (UC)], costly equipment, and inconsistent purification. This review summarizes recent advances in CAR-T exosome biology, scalable production strategies, and combinatorial approaches to overcome immunosuppressive tumor microenvironments (e.g., immune checkpoint inhibitors, cytokine modulation). We also discuss clinical prospects and future directions.